PROJECT ABSTRACT Alcohol abuse and dependence constitute a significant health problem for our veterans and the general society alike. A complex interplay among genetic, environmental and experiential factors is known to govern motivation and regulation of alcohol (ethanol) drinking behavior throughout the addiction process. Chronic excessive ethanol consumption can lead to the development of dependence, and repeated experience with associated withdrawal episodes may constitute a powerful motivational force that contributes to the perpetuation of ethanol use/abuse, as well as enhancing vulnerability to relapse. A wide array of neuroadaptive changes in several key motivational brain systems and pathways are known to play a role in behavioral manifestations of dependence and, in particular, contributing to excessive drinking associated with dependence. Identifying new and novel neuroadaptive mechanisms that are provoked in response to chronic ethanol exposure and withdrawal experience, and that underlie transition to excessive uncontrolled drinking is critical for advancing the field and, ultimately, facilitating development of new and more effective treatments for battling the problem of alcohol addiction. Recently, preclinical and clinical evidence has emerged implicating a role for the neurotrophic factor BDNF (Brain-Derived Neurotrophic Factor) in the homeostatic regulation of various ethanol-related behaviors, including ethanol self-administration behavior. However, relatively few studies have examined the role of BDNF in modulating ethanol drinking in the context of dependence. This proposal is aimed at addressing this void in the literature. During the current funding period, we characterized a mouse model of ethanol dependence that we developed, which involves repeated cycles of chronic ethanol exposure and withdrawal and results in robust escalation of voluntary ethanol drinking. Further, we recently collected some novel preliminary data using our dependence model that provides encouraging support for the notion that changes in brain BDNF expression relate to excessive drinking associated with dependence. Accordingly, a central tenet of this proposal is that adaptive changes in BDNF expression and function in specific brain regions as a consequence of chronic ethanol exposure and withdrawal experience plays a role in mediating and/or promoting excessive drinking associated with dependence. Our experimental strategy and approach for addressing this important research question involves use of our well- characterized mouse model of ethanol dependence and drinking. Proposed studies will examine the effects of repeated cycles of chronic ethanol exposure and withdrawal on time-dependent changes in Bdnf mRNA and BDNF protein expression in two brain structures intimately involved in ethanol dependence and drinking as well as BDNF-mediated behavioral effects: the prefrontal cortex (PFC) and the nucleus accumbens (NAc) (Aim I). A second set of studies will examine whether direct administration of BDNF into the PFC alters ethanol drinking in dependent compared to nondependent mice and whether this effect is selective for ethanol (Aim II). Studies also are proposed to investigate mechanisms underlying the ability of intra-PFC BDNF treatment to modulate ethanol drinking in our model of dependence and drinking (Aim III and Aim IV). These studies will focus on BDNF signaling mechanisms in the PFC and well as potential changes in BDNF activity in the NAc. Thus, this proposed research project will utilize our established mouse model of ethanol dependence and drinking to examine mechanisms by which neuroadaptive changes in BDNF expression and function contribute to escalation of drinking associated with ethanol dependence. As such, the proposal addresses a highly significant and clinically relevant research topic that will provide new information about potential therapeutic targets for treating ethanol dependence and harmful drinking associated with alcoholism.